PROJECT SUMMARY Atopic dermatitis (AD) affects over 9 million children in the U.S. and ranks first among all skin conditions in global disability burden. Atopic dermatitis often heralds the development of several comorbid conditions including asthma, food allergy, skin infections and neurodevelopmental disorders. Because of the significant socioeconomic impact of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on prevention with limited success. Recent advances in cutaneous biology identify epidermal defects and skin barrier dysfunction to be the key initiators of AD and possibly allergic sensitization. Our central hypothesis is that daily emollient use from birth can prevent the development of AD. Recently, our international multi-centered clinical trial found enhancing early skin barrier function with daily emollient use from birth significantly reduces the risk of AD development in high-risk populations by 50%. In this current proposal, to better guide skin care recommendations for all newborns, we extend our approach into a community setting and into newborns unselected for risk. The results of a community-based clinical trial utilizing a pragmatic trial design will be immediately applicable to the population at large and will establish a new standard of care for all newborns. A prevention strategy that reduces AD prevalence by just 20% would save hundreds of millions of dollars annually in U.S. healthcare expenditures and reduce the overall disease burden for millions of children. Under a NIAMS U34 planning grant, our multidisciplinary team spent the last two years creating a clinical trial management infrastructure, developed and refined a study protocol and accompanying regulatory documents, and recruited 25 primary care practices from Oregon, Colorado, Wisconsin, and North Carolina. We are now poised to successfully complete the following aims of the current study: 1) Perform a pragmatic community-based randomized controlled trial investigating whether daily full- body emollient therapy starting in the first 2 months of life prevents atopic dermatitis in a real-world setting and 2) As an exploratory analysis, determine whether a family history of allergic disease and key early life exposures such as pet ownership modify the preventive effect of emollient therapy on AD. Given the experience and expertise of our multi-disciplinary team, we expect to successfully complete both aims of this proposal in the 5-year award period. The expected results from this U01 project represent a major public health breakthrough with the potential for reducing the AD burden on a global scale.